This invention relates to novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. The compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.
Follicle stimulating hormone (FSH) belongs to a family of glycoprotein hormones, which includes lutenizing hormone (LH), thyrotropin (TSH) and chorionic gonadotropin (CG). Each of these hormones is composed of two different non-covalently bound subunits termed xcex1 and xcex2. Within a species the amino acid sequence of the xcex1 subunits for these different hormones is identical, while the hormone specific xcex2 subunits exhibit different amino acid sequences (Combarnous, Endocrine Review, 13:670-691 (1992).
In females, follicle stimulating hormone (FSH) stimulates follicular granulosa cell proliferation in the ovary and impacts synthesis of estrogen, a hormone which is integral to follicular maturation and ovulation. An antagonist of FSH therefore acts to limit proliferation of follicular granulosa cells in the ovary, acting as a contraceptive. The FSH antagonist may also delay the maturation of follicles within the ovary, thereby postponing the maturation of a limited number of follicles in women. Such treatments have the potential for increasing the possibility of natural fertilization and pregnancy later in life.
Because of the controlling function of FSH on estrogen synthesis, an FSH antagonist may also be effective in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer.
An added advantage for an FSH antagonist would be its specific action on ovarian tissue without impact on peripheral tissues containing estrogen receptors. This would be expected to reduce the side effects associated with estrogen receptor antagonists.
Because the proliferation of follicular granulosa cells also impacts the health and development of the oocyte, FSH antagonists may be useful in preventing depletion of oocytes, a common side effect of chemotherapy or similar treatments designed to treat rapidly dividing cells.
In males, follicle stimulating hormone (FSH) is involved in the maturation of sperm cells. More specifically, FSH action in males is directed at the Sertoli cells, which are a recognized target of the hormone and which support the process of sperm maturation (spermatogenesis). FSH antagonists will therefore inhibit sperm maturation without affecting the production of androgens produced from Leydig cells under the control of luteinizing hormone (LH). In addition, FSH receptors have been reported in the epididymis in the male reproductive tract. Thus an FSH antagonist would be expected to affect the viability and motility of sperm by controlling functions of the epididymis.
FSH antagonists also have the potential to modify the rate of germ cell division in males. Because chemotherapy is known to deplete rapidly dividing cells such as spermatocytes, an FSH antagonist may be useful in a planned chemotherapy regimen to prevent spermatocyte depletion.
An FSH antagonist used as a female contraceptive could be used in contraceptive formulations alone or in combination with known contraceptive agents such as progesterone receptor modulators, estrogen receptor modulators, or androgen receptor modulators. An FSH antagonist used as a male contraceptive could be used alone or in combination with androgen receptor modulators, progesterone receptor modulators, or with estrogen receptor modulators. In addition, agents that affect the viability or motility or fertilizability of sperm by acting within the female genital tract may also be used in combination with FSH antagonists concomitantly, or as scheduled in a kit that prevents fertilization during the administration of an FSH antagonist. An example of such an agent is nonoxynol-9.
In recent years, peptide (based) FSH agonists and antagonists have been discovered and developed. Bono, G., et. al., in WO 97/12038 disclose novel amino acid residue peptide useful in stimulating FSH enhancement.
Amino acid based sulfonamide derivatives have also been developed for the treatment of a variety of conditions and disorders. Dumont, R. in WO 93/05014 discloses sulfonamide derivatives useful as inhibitors of Ca+2 dependent enzymes.
The compounds of the present invention are non-peptide antagonists of FSH useful in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; prevention of depletion of oocytes (a common side effect of chemotherapy or similar treatment); female and male contraception; and prevention of spermatocyte depletion.
Additionally, the generation of chemical libraries on and off solid resins has proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTPS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of xe2x80x9clead compoundsxe2x80x9d is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity.
Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.
The present invention is directed to compounds of the formula (I) 
wherein
R1 and R2 are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkylcarbonyl, C1-C6perhaloalkyl, phenyl, phenylC1-C6alkyl-, phenylcarbonyl-, pyridyl, pyridylC1-C6alkyl-, pyridylcabonyl-, thienyl, thienylC1-C6alkyl- and thienylcarbonyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy or NO2;
R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C4alkenyl and C2-C4alkynyl, where the C1-C6alkyl is optionally substituted with a phenyl, pyridyl, thienyl or furyl, wherein the phenyl, pyridyl, thienyl or furyl is optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy or NO2;
R4 is selected from the group consisting of xe2x80x94C2-C6alkyl-, -cyclopentyl-, -cylcohexyl-, -cyclohexyl-CH2xe2x80x94, xe2x80x94CH2-cyclohexyl-CH2xe2x80x94, xe2x80x94CH2-phenyl-CH2xe2x80x94, xe2x80x94C(O)xe2x80x94CH2-phenyl-CH2xe2x80x94, xe2x80x94C(O)xe2x80x94C1-C6alkyl- and -cyclohexyl-CH2-cyclohexyl-;
where the R4 substituent is inserted into the compound of formula (I) from left to right, as defined;
alternately, R2, R3, and R4 can be taken together with the two N atoms of the diamine portion of the molecule to form 
alternately, R3 can be taken together with R2 as xe2x80x94C2-C3alkyl-, provided that R4 is xe2x80x94C2-C6alkyl-;
L is selected from the group consisting of xe2x80x94C3-C6cycloalkyl (wherein the cycloalkyl is substituted with R5 and R6), a bicyclic compound of the form 
(wherein the point of the attachment of the bicyclic compound is any carbon atom of the alkyl portion and wherein the aromatic portion of the bicyclic compound is optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NO2, acetamido, xe2x80x94NH2, xe2x80x94NH(C1-C6alkyl) or xe2x80x94N(C1-C6alkyl)2), and xe2x80x94(CH2)m-CR8R5R6;
m is 0 to 3;
R5 is selected from the group consisting of phenyl, naphthyl, (wherein the phenyl and naphthyl may be optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NO2, acetamido, xe2x80x94NH2, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)2, C1-C6alkylcarbonylamino or C1-C6alkylsulfonylamino), bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, C3-C6cyloalkenyl, (wherein the cycloalkenyl group contains one or two double bonds), a six membered heteroaryl (wherein the six membered heteroaryl contains one to three N atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy or NO2;
R6 is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, hydroxy and phenyl, (wherein the phenyl may be optionally substituted with one to three substituents independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or trifluoromethoxyl); provided that R6 may be phenyl only when R5 is phenyl;
R8 is selected from the group consisting of hydrogen and C1-C6alkyl;
Z is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94C(xe2x95x90O)NHxe2x80x94;
p is 0 to 1;
is selected from the group consisting of phenyl, naphthyl, quinolinyl, thienyl, and furyl;
X is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NO2, acetamido, xe2x80x94NH2, xe2x80x94NH (C1-C6alkyl) and xe2x80x94N(C1-C6alkyl)2;
n is 0 to 3;
Y is selected from the group consisting of phenyl, xe2x80x94Oxe2x80x94phenyl, xe2x80x94NHxe2x80x94phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, NO2, cyano, methylthio, acetamido, formyl, -amino, -aminocarbonyl, xe2x80x94NHxe2x80x94C1-C6alkyl, xe2x80x94N(C1-C6alkyl)2, xe2x80x94COOH, xe2x80x94COO(C1-C6alkyl), xe2x80x94COO(C1-C6alkylphenyl), C1-C6alkylcarbonylamino, C1-C6alkylaminocarbonyl, di(C1-C6alkyl)aminocarbonyl, aminosulfonyl, C1-C6alkylaminosulfonyl or di(C1-C6alkyl)aminosulfonyl), biphenyl, 3,4-methylenedioxyphenyl, dianthrenyl, dibenzothienyl, phenoxathiinyl, a six membered heteroaryl (wherein the six membered heteroaryl contains one to three nitrogen atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen atom, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents selected from halogen, C1-C6alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, formyl, NO2, cyano, methylthio, acetamido, -amino, -aminocarbonyl, xe2x80x94NH C1-C6alkyl, xe2x80x94N(C1-C6alkyl)2, xe2x80x94COOH, xe2x80x94COO(C1-C6alkyl), or xe2x80x94COO(C1-C6alkylphenyl));
q is 0 to 1;
provided that when q is 1, n is 0;
and stereoisomers and pharmaceutically acceptable salts or esters thereof.
The compounds of formula (I) that comprise this invention may be prepared using a process wherein the compound is synthesized on a solid support resin, followed by cleavage of the compound from the resin support, as a final isolation step. The various substituents described in formula (I) may be present initially on the reagents employed to prepare the compounds of formula (I). In some instances they may be conveniently added following cleavage. In those cases where the substituents are present on the reagents, care must be taken in the selection of the resin to insure that the substituents are compatible with the selected resin.
One method for producing the compounds of formula (I) involves synthesis, on resin, of three intermediates, followed by cleavage of the resin to yield the desired product, as outlined in Scheme 1.
The solid support resin, herein represented by the symbol  is typically polystyrene, and is terminated with a reactive functional group. There are a number of commercially available resins, with a variety of terminating groups. Suitable examples of support resins for preparation of compounds of formula (I) include: Wang resin (Wang, S. S., J. Am. Chem. Soc., 95, 1328 (1973); Kiselov, A. S. and Amstrong, R. W., Tetrahedron Letter, 318, 6163 (1997)), [wherein the terminating group is xe2x80x94(p-phenyl)xe2x80x94CH2xe2x80x94Oxe2x80x94(p-phenyl)xe2x80x94CH2xe2x80x94OH]; RAPP Tentagel SAM resin (Rotte, B., et.al., Collect. Czech. Chem. Commun., 61, 5304 (1996)), [wherein the terminating group is xe2x80x94(p-phenyl)xe2x80x94CH2xe2x80x94Oxe2x80x94(p-phenyl)xe2x80x94CH2xe2x80x94NH2]; vinylsulfonyl resin (Kroll, F. E., et. al., Tetrahedron Lett., 38, 8573, 1997), [wherein the terminating group is xe2x80x94(p-phenyl)xe2x80x94CH2xe2x80x94SO2xe2x80x94CHxe2x95x90CH2]; rink amide resin (Rink, H., Tetrahedron Lett., 28, 3787, 1987; Brown, E. G. and Nuss, J. M., Tetrahedron Lett., 38, 8457, 1997), [wherein the terminating group is xe2x80x94CH2xe2x80x94Oxe2x80x94(p-phenyl)xe2x80x94CH2(NHxe2x80x94Fmoc)-(2,4-dimethoxyphenyl)]; FMPB resin (4-(4-formyl-3-methoxyphenoxy)butyryl AM resin) (Bilodeau, M. T. and Cunningham, A. M., J. Org. Chem., 63, 2800, 1998; Kearny, P. T., et. al., J. Org. Chem., 63, 196, 1998) [wherein the terminating group is an aldehyde]; and the like. The appropriate selection of solid support resin and terminating group is based on the synthesis steps, reaction conditions and final compound substituents; and may be determined by one skilled in the art.
The selected resin and appropriate reactants are employed to prepare resin bound, substituted diamines of formula (II): 
Broadly, there are three approaches described herein to obtain the resin bound substituted diamines of formula (II). In the first approach a commercial resin capable of direct coupling reactions to an appropriately substituted diamine is purchased and reacted to produce the compound of formula (II). In the second approach, a commercial resin is suitably activated to react with an appropriately substituted diamine. This approach is advantageously employed in those cases where the purchased resin is not amine terminated. In the third approach, a commercially available amine terminated resin is reacted with a substituted and protected amine alcohol to form the resin substituted diamine of formula (II). In this third approach, the terminal amine of the selected resin is incorporated into the end product compound.
Specifically, compounds of formula (II) wherein R2 and R3 are hydrogen; wherein R2 and R3 are taken together as xe2x80x94C2-C3alkyl and R4 is other than C(O)xe2x80x94CH2-phenyl-CH2xe2x80x94 or C(O)xe2x80x94C1-C6alkyl-; and wherein R2, R3 and R4 are taken together with the two N atoms of the diamine portion of the molecule to form 
may be prepared as outlined in Scheme 2 below: 
According to Scheme 2, a commercially available, OH terminated resin is coupled with 4-nitrophenyl chloroformate, in an organic solvent such as DCM, DCE, and the like, preferably DCM, in the presence of an amine base, such as pyridine, N-methylmorpholine (NMM), triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably N-methylmorpholine (NMM), preferably at room temperature, to incorporate the xe2x80x94C(O)xe2x80x94Oxe2x80x94(p-nitrophenyl)xe2x80x94 group into the resin, to form the corresponding p-nitrophenol carbonate terminated resin.
The p-nitrophenol group on the p-nitrophenol carbonate terminated resin is next displaced with a suitably substituted linear diamine of formula (V), a suitably substituted cyclic diamine of formula (VI), or a suitably substituted bicyclic heterocyclyl diamine of formula (VII), in an organic solvent such as DMF, DMAC, DCM, DCE, and the like, preferably at room temperature, to form the corresponding resin bound substituted diamine of formula (IIa), (IIb) or (IIc), respectively.
Alternately, compounds of formula (II), wherein R2 and R3 are hydrogen may be prepared according to the process outlined in Scheme 3.
Accordingly, a commercially available, vinylsulfonyl terminated resin is coupled with a suitably substituted linear diamine of formula (V), in an organic solvent such as DMF, overnight, at room temperature, to produce the resin bound substituted diamine of formula (IId). In this approach, the amine group is coupled directly to the terminal methylene group of the vinylsulfonyl terminated resin.
Compounds of formula (II) wherein R3 is hydrogen and R4 is selected from C(O)xe2x80x94CH2-phenyl-CH2xe2x80x94 or C(O)xe2x80x94C1-C6alkyl- may be prepared according to the process outlined in Scheme 4.
When R2 is other than hydrogen, a commercially available amine terminated resin is reacted with a suitably substituted aldehyde of formula (VIII), in an organic solvent such as DCM, DCE, and the like, in the presence of a catalyst such as sodium cyanoborohydride, sodium triacetoxyborohydride and the like, preferably sodium triacetoxyborohydride, preferably at room temperature, to produce the corresponding substituted amine terminated resin of formula (IX).
The substituted amine terminated resin of formula (IX) is coupled with a suitably substituted Fmoc-protected amine alcohol, a compound of formula (X), in an organic solvent such as DMF, DMAC, DCM, and the like, preferably DMF, preferably at room temperature, to produce the corresponding resin bound Fmoc-protected, substituted diamine of formula (XI). The Fmoc protecting group on the resin bound substituted diamine of formula (XI) is then removed using 20% piperidine in DMF, preferably at room temperature, to produce the corresponding resin bound, substituted diamine of formula (IIe).
Compounds of formula (II) wherein R3 is other than hydrogen may be prepared according to the process outlined in Scheme 5.
A resin bound substituted diamine of formula (IIe) is coupled with a suitably substituted aldehyde of formula (XII), in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydide, and the like, preferably triacetoxyborohydride, in an organic solvent such as DCM, DCE, and the like, preferably DCE, preferably at room temperature, to produce the corresponding resin bound substituted diamine of formula (II).
The resin bound, substituted diamines of formula (II) are next reacted with suitably substituted reagents to produce the corresponding resin bound, substituted secondary amine of formula (III): 
In a general approach to producing the resin bound substituted triamine of formula (III), bromoacetic acid is initially coupled to the diamine for formula (II), followed by coupling of a suitably substituted amine.
More specifically, in this approach, compounds of formula (III) may be prepared according to the process outlined in Scheme 6. This approach is also particularly advantageous in the preparation of compounds of formula (I) wherein L is xe2x80x94C3-C6cycloalkyl. 
Accordingly, a resin bound, substituted diamine of formula (II) is coupled with bromoacetic acid, using a coupling agent such as diisopropyl carbodiimide, 1,1xe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiamide, and the like, preferably diisopropylcarbodiamide, in a solvent such as DMF, DMAC, and the like, preferably DMF, preferably at room temperature, to form the corresponding resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII).
The bromine on the resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII) is then displaced with a suitably substituted amine of formula (XIV), in a solvent such as DMSO, preferably at room temperature, to form the corresponding resin bound, substituted secondary amine of formula (III).
The resin bound, substituted secondary amine of formula (III) is subsequently reacted with suitably substituted reagents to produce the corresponding resin bound, compound of formula (IV): 
The resin bound compound of formula (IV) may be prepared via two processes. In the first process, the resin bound, substituted secondary amine of formula (III) is directly coupled with a suitably substituted sulfonyl chloride, suitably substituted carbonyl chloride or suitably substituted isocyanate reagent to prepared the end product compound. In the second process, the resin bound, substituted secondary amine of formula (III) is first coupled with a halogen substituted aryl or heteroaryl sulfonyl chloride, followed by displacement of the halogen with a suitably substituted aryl or heteroaryl substituted boronic acid, to yield the end product compound.
More particularly, in the first process, the resin bound compound of formula (IV) is prepared as outlined in Scheme 7.
According to the first process, the resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted chloride of formula (XV), or a suitably substituted isocyanate of formula (XVI), in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine (NMM), triethyl amine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound compound of formula (IV).
The second process is particularly advantageous for preparation of compounds of formula (I) wherein Z is sulfonyl, n is 0, q is 1 and the 
substituent is phenyl, napthyl, thienyl or furyl. The second process is also particularly advantageous for preparation of compounds of formula (I) wherein R2 and R3 are taken together as C2-C3alkyl and Z is sulfonyl; and wherein R2, R3, and R4 are taken together with the two N atoms of the diamine portion of the molecule to form 
In the second process, the resin bound compound of formula (IV) is prepared via the process outlined in Scheme 8.
The resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted aryl or heteroaryl sulfonyl chloride of formula (XVII), wherein A represents a halogen selected from chlorine, bromine or iodine, preferably bromine, in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine, triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound, substituted sulfonyl compound of formula (XVIII).
On the resin bound, substituted sulfonyl of formula (XVIII), the halogen represented by A is next displaced with a suitably substituted boronic acid of formula (XIX), using Suzuki conditions (in a solvent such as dimethoxyethane (DME), dioxane, and the like, in the presence of a base such as 2M sodium carbonate, tetramethylguanadine (TMG), and the like, under a N2 atmosphere, at a temperature in the range of about 80-100xc2x0 C., in the presence of a catalyst, such as palladium tetrakistriphenylphosphine), to form the corresponding resin bound, substituted sulfonamide formula (IVa).
The resin bound compound of formula (IV), may next be treated to yield the corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 90:10 TFA:water, preferably at room temperature, to produce the corresponding compound of formula (I).
A resin bound compound of formula (IVa) may alternatively be further reacted with a suitably substituted compound of formula (XX) and/or formula (XXI), wherein J is bromine or iodine, to incorporate R1 and R2 substituents, wherein R1=R2 and are other than hydrogen. For this process, the preferred resin is the vinylsulfonyl terminated resin, R4 is other than xe2x80x94C(O)xe2x80x94CH2-phenyl- or xe2x80x94C(O)-C1-C6alkyl-, and the R1 and R2 substituents are incorporated according to the process outlined in Scheme 9.
Accordingly, a resin bound compound of formula (IVa) is reacted with a suitably substituted compound of formula (XX) and/or formula (XXI), wherein J is bromine or iodine, preferably at room temperature, to produce the corresponding resin bound, quaternary amine of formula (XXII).
The resin bound quaternary amine of formula (XXVI) is then treated to yield the desired corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 20% DIEA in DMF, preferably at room temperature, to produce the corresponding compound of formula (I).
In an alternative scheme for producing compounds of formula (I) wherein R1 and/or R2 are other than hydrogen, the R1 and R2 substituents may be introduced following cleavage of the resin bound compound of formula (IV). More particularly, such a process is as outlined in Scheme 10.
A compound of formula (Ia), wherein R1 and R2 are hydrogen, is treated with a suitably substituted aldehyde of formula (XXIII), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, and then with a suitably substituted aldehyde of formula (XXIV), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, to produce the corresponding compound of formula (I).
In an alternative method of Scheme 10, compounds of formula (I), wherein R1 and R2 are the same and other than hydrogen, are produced by treating the compound of formula (Ia) with at least two molar equivalents of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to produce the corresponding product of formula (I).
In another alternative method of Scheme 10, compounds of formula (I), wherein one of R1 or R2 is hydrogen, the compound of formula (Ia) is treated with at least one molar equivalent of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to yield the desired corresponding compound of formula (I).
Compounds of formula (I), wherein R1 and/or R2 is alkylcarbonyl may be prepared according to the process outlined in Scheme 11.
Accordingly, a suitably substituted compound of formula (Ia), wherein R1 and R2 are each hydrogen, is treated with a suitably substituted acid chloride of formula (XXV), preferably in the amount of at least one molar equivalent, in an organic solvent such as chloroform, DCM, and the like, in the presence of a organic base such as TEA, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib). Alternatively, a suitably substituted compound of formula (Ia), wherein R1 and R2 are each hydrogen, is treated with a suitably substituted carboxylic acid of formula (XXVI), preferably in the amount of at least one molar equivalent, in an organic solvent such as DMF, and the like, in the presence of a coupling agent such as DIC, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib).
As used herein, unless otherwise noted, xe2x80x9calkylxe2x80x9d whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 6 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, hexyl and the like. Similarly, the term xe2x80x9ccycloalkylxe2x80x9d shall include saturated alkyl ring structures containing 3 to 6 carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl and cylcohexyl.
As used herein, unless otherwise noted, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d shall include straight and branched chain alkene and alkyne having 1 to 6 carbon atoms, for example allyl, vinyl, 2-propenyl, 2-propynyl, and the like.
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, propoxy, sec-butoxy, t-butoxy, 2-methyl-3-bytoxy and the like.
As used herein the terms xe2x80x9caromatic and arylxe2x80x9d shall denote phenyl and naphthyl.
Suitable xe2x80x9csix membered heteroaryls containing one to three nitrogen atomsxe2x80x9d include pyridyl, pyridizanyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl.
Suitable xe2x80x9cfive membered heteroaryl containing one sulfur, oxygen or nitrogen atom, optionally containing one to three additional nitrogen atomsxe2x80x9d include thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and the like.
As used herein, unless otherwise noted, xe2x80x9chalogenxe2x80x9d shall denote chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, xe2x80x9c*xe2x80x9d represents the presence of a stereogenic center.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenylC1-C6alkylamidoC1-C6alkylxe2x80x9d substituent refers to a group of the formula 
In a preferred embodiment of the present invention are compounds of the formula (I) wherein
R1 and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, methylcarbonyl, trifluoromethyl, phenyl, benzyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, thienyl, thienylmethyl and thienylcarbonyl (where the phenyl, pyridyl or thienyl is optionally substituted with one to two substituents independently selected from halogen, C1-C3alkyl, C1xe2x80x94C3alkoxy, trifluoromethyl, trifluoromethoxy or nitro); and
R3 is selected from the group consisting of hydrogen, methyl, xe2x80x94CHxe2x95x90CHxe2x80x94 (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl, trifluoromethoxy and nitro), xe2x80x94Cxe2x89xa1Cxe2x80x94, (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl, trifluoromethoxy and nitro).
More preferably, R1, R2, and R3 are the same; most preferably R1, R2 and R3 are the same and are hydrogen.
In another preferred embodiment of the present invention are compounds of the formula (I) wherein R2 and R3 are taken together as C2-C3alkyl, more preferably 1,2-ethyl; and R4 is C2-C6alkyl, more preferably 1,2-ethyl or 1,3-n-propyl.
In another preferred embodiment of the present invention are compounds of the formula (I) wherein R2, R3, and R4 are taken together with the two N atoms of the diamine portion of the molecule to form 
Preferred R4 substituents include xe2x80x94C2-C6alkyl, -cyclohexyl, xe2x80x94CH2-cyclohexylxe2x80x94CH2, -cyclohexylxe2x80x94CH2-cyclohexyl and xe2x80x94CH2-phenylxe2x80x94CH2.
In another preferred embodiment of the invention are compounds of the formula (I) wherein R2, R3, and R4 may be taken together with the two N atoms of the diamine portion of the molecule to form 4,4xe2x80x2-bipiperidinyl.
Preferred L substituents include -cyclopropyl-, cyclohexyl-, (wherein the cylcopropyl or cyclohexyl is substituted with R5 and R6), 
and (CH2)mxe2x80x94CR8R5R6.
Preferred R5 substituents include phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl, trifluoromethoxy, methylcarbonylamino, methylsulfonylamino, nitro, acetomido, amino, C1-C3alkylamino or di(C1-C3alkyl)amino), N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, C3-C6cycloalkenyl (wherein the cycloalkenyl contains one or two double bonds), thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl and triazinyl.
Preferred R6 substituents include hydrogen, C1-C3alkyl, cyclopropyl, cyclobutyl, cyclohexyl, C1-C3alkoxy, hydroxy and phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl or trifluoromethoxy); provided that R6 is phenyl only when R5 is phenyl.
Preferred R8 substituents include hydrogen and C1-C3alkyl.
Preferably Z is selected from the group consisting of SO2, C(xe2x95x90O) and xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94.
Preferred 
substituents include phenyl, naphthyl, quinolinyl and thienyl.
Preferably n is 0 to 2.
Preferred X substituents include halogen, C1-C6alkyl, C1-C4alkoxy, trifluoromethyl, trifluoromethoxy, nitro, acetamido, amino, C1-C3alkylamino and di(C1-C3alkyl)amino.
Preferred Y substituents include phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C1-C3alkylamino, di(C1-C3alkyl)amino, carboxy, xe2x80x94COO(C1-C3alkyl), xe2x80x94COO(C1-C3alkylphenyl), C1-4alkylaminosulfonyl, C1-C4alkylcarbonylamino), biphenyl, 3,4-methylenedioxyphenyl, dianthryl, dibenzothienyl, phenoxathiinyl, a five membered heteroaryl (wherein the five membered heteroaryl contains one nitrogen, oxygen or sulfur atom and optionally contains an additional nitrogen or oxygen atom) and a six membered heteroaryl (wherein the six membered heteroaryl contains one nitrogen atom and optionally contains an additional nitrogen or oxygen atom); wherein the five or six membered heteroaryl is optionally substituted with one to two substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C1-C3alkylamino or di(C1-C3alkyl)amino; and wherein the point of attachment for the five or six membered heteroaryl is a carbon atom.
Particularly preferred compounds of the present invention are listed in Table 1, below.
In a particularly preferred embodiment of the present invention are compounds of the formula (I) as enumerated in Table 2 below:
For the compounds listed in Table 3 below, as well as all compounds listed in Table 1 and 2 above, structures were confirmed via molecular weight determination using an electro-spray mass spectrometer in positive mode and via HPLC retention time on a reversed phase column.
The salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
The pharmaceutically acceptable esters of the novel compounds of the present invention include such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,43, Column 9, line 61 ot Column 12, line 51, which is incorporated herein by reference. Included within such pharmaceutically acceptable esters are those hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and those described I detail in U.S. Pat. No. 4,479,947, which is incorporated herein by reference.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
The substituted aminoalkylamide derivatives of this invention are capable of inhibiting follicle stimulating hormone (FSH) to achieve the desired pharmacological effect. With an effective amount of the substituted aminoalkylamide derivative compounds dispersed in a pharmaceutical composition as an active ingredient, the pharmaceutical composition is introduced as a unit dose into an afflicted mammal.
The term xe2x80x9cunit dosagexe2x80x9d and its grammatical equivalent is used herein to refer to physically discrete units suitable as unitary dosages for human patients and other warm blooded mammals, each unit containing a predetermined effective, pharmacologic amount of the active ingredient calculated to produce the desired pharmacological effect in association with the required physiologically tolerable carrier, e.g., a diluent or a vehicle. The specifications for the novel unit dosage forms suitable for use herein are dictated by and are directly dependent on (a) the unique characteristics of the active ingredient, and (b) the limitations inherent in the art of compounding such an active ingredient for therapeutic use in humans and other mammals. Examples of suitable unit dosage form in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation and the like. The active ingredient is referred to herein as being dispersed in the carrier. The dispersion form can be a simple admixture, a non-settling dispersion as in the case of certain emulsions, or as an ultimate dispersion, a true solution.
The amount of active ingredient that is administered in vivo depends on the age and weight of the mammal treated, the particular medical condition to be treated, the frequency of administration, and the route of administration. The dose range can be about 0.01 to about 500 milligrams per kilogram of body weight, more preferably about 0.1 to about 50 milligrams per kilogram of body weight and most preferably about 0.1 to about 25 milligrams per kilogram of body weight. The human adult dose is in the range of about 10 to about 2000 milligrams daily, given as a single dose or in 3 or 4 divided doses. Veterinary dosages correspond to human dosages with the amounts administered being in proportion to the weight of the animal as compared to adult humans. When the compounds are employed to treat FSH receptor mediated diseases or disorders the dosage range can be about 0.01 to about 200 mg/kg. The preferred dosage range is from about 0.5 to about 100 mg/kg.
Physiologically tolerable carriers are well known in the art. Carriers may be divided into liquid and solid carriers.
Exemplary of liquid carriers are aqueous solutions that contain no materials in addition to the substituted aminoalkylamide derivative compound, or contain a buffer such as sodium phosphate ay a physiological pH value, saline and the like. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin and vegetable oils such as cottonseed oil.
Exemplary solid carriers (diluents) include those materials usually used in the manufacture of pills or tablets, and include corn starch, lactose, dicalcium phosphate, thickeners, such as tragacanth and methylcellulose U.S.P., finely divided SiO2, polyvinylpyrrolidone, magnesium stearate and the like. Antioxidants such as methylparaben and propylparaben can be present in both solid and liquid compositions, as can sweeteners such as cane or beet sugar, sodium saccharin, sodium cyclamate and the dipeptide methyl ester sweetener sold under the trademark NUTRASWEET (aspartame) by G. D. Searle Co.
The pharmaceutical composition can be administered orally, topically or by injection, by means well known in the art. In preferred practice, the composition is administered orally as a tablet, capsule or aqueous dispersion. The pharmaceutical composition is maintained within the mammal until the substituted aminoalkylamide derivative compound is cleared from the mammal""s body by natural means such as excretion or metabolism.
Compositions for injection may be prepared in unit dosage form in ampules or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents. Alternatively, the active ingredient may be in a powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. Topical formulations may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Inasmuch as a pharmaceutical composition can be administered 3 to 4 times daily (per 24 hour period), the method of treating a disorder of condition mediated by FSH can include administering the pharmaceutical composition a plurality of times into the treated mammal over a time period of weeks, months and years.
Disorders or conditions mediated by the FSH receptor include uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; depletion of oocytes (a common side effect of chemotherapy or similar treatment); spermatocyte depletion; or for female and male contraception.
The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.